Method for preparing a biomaterial based on hydroxyapatite, resulting biomaterial and surgical or dental use

ABSTRACT

A solid powder product with a Ca/P ratio of between 1.40 and 1.90 is prepared from tricalcium phosphate and tetracalcium phosphate. An aqueous solution containing calcium ions and phosphate ions with a Ca/P ratio higher than 0.20 and lower than 0.50 is prepared. The aqueous solution and the solid powder product and optionally water are mixed to obtain a mixture with a liquid/solid weight ratio of between 0.30 and 0.65 and a resulting paste with a Ca/P ratio of between 1.50 and 1.67.

This application is a 371 of PCT/FR99/00595, filed on Mar. 17, 1999.

FIELD OF THE INVENTION

The invention relates to a process for the production of a biomaterialessentially constituted of phosphocalcium hydroxyapatite of an atomicratio of Ca/P comprised between 1.50 and 1.67. The invention relates tothe obtained biomaterial and to uses of the latter, in particular fordental or bone filling or restoration. The invention also relates tosurgical or dental set for practicing this invention.

BACKGROUND OF THE INVENTION

Phosphocalcium hydroxyapatites are well known and more and more used inthe surgical or dental field because of their properties ofbiocompatibility and osteoconduction. They can be used in the dentalfield for periodontal filling, restoration of bone crests, filling cystsor recesses after dental extraction . . . and, in orthopedic surgery,for filling bone defects, interstitial filling between prosthesis andcortical bone, injection into vertebral bodies . . . The material thusemplaced can if desired contain active substances which, after hardeningin situ of the material, are slowly diffused.

The preparation of phosphocalcium hydroxyapatites is essentially carriedout according to two different ways each leading to specificapplications:

on the one hand, an in situ preparation, in which the hardening of thehydroxyapatite is effected on the site of use at low temperature (inparticular in vivo at body temperature), this preparation permitting thepractice of the mentioned surgical or dental applications (thispreparation which has a hardening phase at the site of utilization isdesignated hereafter as “preparation in situ” even if certain phases canbe carried out apart from the utilization site),

on the other hand, an industrial preparation producing eitherpulverulent apatites or slightly bonded ones having limited mechanicalproperties, or ceramic apatites after high temperature thermal treatmentor compression treatment in the presence of a binder.

The industrial apatites described above, which have good mechanicalproperties, are of course useless in applications in which a surgical ora bone operating site of any type must be filled or restored, becausethey require, to obtain their hardening, an industrial treatment undersevere conditions. Moreover, industrial calcine apatites are alwaysstoichiometric and have a low specific surface (less than 10 m²/g) andlow solubility (solubility product equal to 10⁻¹¹⁹): these propertiesrender the material difficultly bioresorbable, which represents adrawback in most of the surgical or dental applications (in which a slowreplacement by bone of the implanted material is generally sought).

The present invention relates to apatites “prepared in situ”, that iswhose hardening can be carried out at low temperature in situ at theutilization site. Of course, these apatites can, as the case may be, beused in other applications such as those of industrial apatites.

Known apatites for in situ preparation are generally prepared as cementsby mixing with water a powder containing one or more calcium phosphatesselected from known phosphates: monocalcium phosphate hydrated or not,dicalcium phosphate hydrated or not, tricalcium phosphate α or β,tetracalcium phosphate (U.S. Pat. No. 461,053, EP 0 416 761, FR2.693.716 . . . ). Certain authors have proposed first dissolving inwater for mixing monocalcium phosphate so as to avoid untimely hydrationof this phosphate in the powder (WO 95/083149). The apatites obtained bythese known methods have essentially major drawbacks. In the firstplace, their mechanical properties are mediocre (compressive resistanceof the order of 5 to 8 Megapascals), which, in numerous cases, is amajor drawback (periodontal filling, injection in vertebral bodies,interstitial filling for sealing prostheses, osteotomy wedges hardenedin situ . . . ).

Moreover, there is often seen with these known products the formation of“lumps”, of non-reproducible setup times, and an exfoliation of thematerial after its in vivo emplacement because of the biological liquidspresent; certain faults lead either to grave difficulties foremplacement, or to a mediocre quality of the obtained implant (badfilling, bad adherence at the operating site), or a very troublesomeproduction of exfoliated particles outside the operating site. This isparticularly serious in surgery and leads many surgeons to reject thistype of product after one or more unfortunate experiences.

SUMMARY OF THE INVENTION

The present invention provides a process for the in situ preparation ofan apatite biomaterial, having good reproducibility and more certain andeasy use than the known processes (homogeneity of the product, constantsetup time, ease of shaping and modeling, absence of exfoliation).

Another object is to permit obtaining a biomaterial having improvedmechanical properties relative to the known apatite materials preparedin situ.

Another object is to permit obtaining a biomaterial having a solubilityand a specific surface significantly greater than the existing apatitebiomaterials.

An object of the invention is in particularly to provide an apatitematerial which combines excellent properties of resistance tocompression, good solubility in life media and a high specific surface.

To this end, the process contemplated by the invention for preparing abiomaterial whose hardening takes place at the site of utilization, inparticular cold on a surgical or dental operating site (temperaturebelow about 40° C.), is of the type in which are mixed calciumphosphates to obtain a hydroxy apatite within an atomic ratio Ca/Pcomprised between 1.50 and 1.67; the process of the invention ischaracterized in that:

a) there is first prepared a solid pulverulent product from a tricalciumphosphate powder and from a tetracalcium phosphate powder by mixing saidpowders so that the atomic ratio Ca/P of the obtained product will besubstantially comprised between 1.40 and 1.90,

b) there is prepared an aqueous solution or aqueous solutions to mixwith said solid pulverulent product, said solution or solutionscontaining calcium ions and phosphate ions such that the overall atomicratio Ca/P of the solutions will be greater than 0.20 and that theatomic ratio Ca/P of each solution will be less than 0.50,

c) the aqueous solution or solutions and the solid pulverulent productare mixed, with the addition of water as the case may be, such that theliquid/solid weight ratio of the final mixture obtained will becomprised between 0.30 and 0.65 so as to obtain a homogeneous paste ofan atomic ratio Ca/P comprised between 1.50 and 1.67, said paste beingemplaced at the utilization site for its hardening in situ.

Experience has shown that this preparation from, on the one hand, asolid pulverulent product containing tricalcium phosphate andtetracalcium phosphate, on the other hand, from an aqueous solutioncontaining calcium ions and phosphate ions, results in obtaining anaturally homogeneous pasty mixture having no tendency to lump, andhaving progressive and regular setting up and a constant setup time (fora given composition), with the four-fold condition that:

The Ca/P ratio of the solid pulverulent product be comprised in theabove-indicated range (preferably between 1.70 and 1.85),

The Ca/P ratio of the solution or of each solution if several solutionsare used, will be less than 0.50 (preferably less than 0.40),

The Ca/P ratio of the solution, or the overall Ca/P ratio of theassembly of the solutions if several solutions are used, be greater than0.20 (preferably greater than 0.35),

The liquid/solid weight ratio of the produced mixture is comprisedbetween 0.30 and 0.65.

The malleable pasty mixture thus obtained is deposited at theutilization site at which it undergoes setting and at which it thenproceeds to harden. The utilization site can be a surgical or dentaloperating site and the setting up and hardening take place at bodytemperature (temperature below 40° C.). The site can also be a mold toproduce a piece, the setting up and hardening being accomplished cold orat low temperature (particular below 90° C.) so as to increase the speedof hardening. The duration of setting can vary between 10 and 45 minutesas a function of the composition in the above-identified ranges. Thehardening leading to final properties of the biomaterial is obtained atthe end of a period of two to four hours at body temperature and severalhours at a temperature comprised between 60° C. and 100° C. Analyses ofthe obtained biomaterial have shown that the latter is essentiallyconstituted by a microcrystalline hydroxy apatite of atomic ratio Ca/Pcomprised between 1.50 and 1.67, having in combination the followingcharacteristics:

compressive resistance substantially comprised between 15 and 25Megapascals,

solubility corresponding to a solubility product comprised between 10⁻⁹⁴and 10⁻¹⁰⁰,

and a specific surface substantially comprised between 20 and 120 m²/g.

Compressive tests were carried out on cements shaped with “Plexiglas”molds 6 mm in diameter and 6 mm high. After shaping, the molds areplaced in deionized water at 37° C. After 24 hours, the cements aredemolded then kept under the same conditions (water at 37° C.). Testswere carried out at the end of 26 days of maturing. Before thecompressive tests, the specimens were dried. The compressive test iscarried out by subjecting the cylindrical specimen to two oppositecoaxial forces by placing it between the plates of a press. The specimenis subjected to a uniaxial stress which is supplied at a constant speedof 0.5 mm/min. An associated software permits tracing directly thestress as a function of the amount of deformation. Rupture is determinedby an abrupt change in the shape of the curve.

Solubility is determined by suspending in demineralized and decarbonatedwater (100 ml) a predetermined quantity of cement (50 mg) of agranulometry comprised between 20 and 50 microns. The suspension isagitated several times per day for 30 days. At the end of this period,the pH is measured and sampling is carried out to determined by ICPMSthe phosphorus and the calcium. The solubility product can then bedetermined by computation.

Measurement of the specific surface is carried out by an analyzer of the“Micrometrics Flow Sorb II 2300”, on a specimen of crushed cement.

No known apatite material combines all of these properties which can beessential in a large number of applications, in particular surgery anddentistry. Moreover, this material has a microporosity of the order of30% to 55%, which is remarkable, given its mechanical properties. Thisporosity (known per se) permits the circulation of biological fluids inin vivo uses, which promotes the biointegration of the biomaterial andits bioresorbability over time.

It appears that the mentioned advantages of the process and theproperties of the obtained biomaterial result from the intermediateformation, during mixing and setting up, of grains of large constantsize, which, upon their evolution to apatite, lead to a morphology oflarge regular interlock needles. This interlocking of needles gives themechanical properties, the porosity and the surface properties.

So as to facilitate the work of the practitioner, in particular insurgical and dental applications, the solid pulverulent product and theaqueous solution are prepared batchwise in separate contains such thatthe overall liquid/solid weight proportion will be comprised between0.30 and 0.65 and that the overall atomic ratio Ca/P will be comprisedbetween 1.50 and 1.67. It suffices for the practitioner to mix thebatches homogeneously without the addition of water, to obtain a pasteready to use at the utilization site; preferably, the liquid batch willbe mixed with the solid batch as required by the mixture.

The solid pulverulent solid is preferably first treated so that the meandiameter of the grains D₅₀ will be comprised between 15 and 20 micronsand that its cross-sectional diameter D₉₅ will be equal to 100 microns.There is thus avoided the presence of large size grains which couldpromote the formation of lumps; moreover, such a narrow granulometricdistribution (homogenous fine grains) contributes to the production of aprogressive and regular setting up, which is perfectly reproducible.

DETAILED DESCRIPTION OF THE INVENTION

According to a preferred embodiment, there is prepared the solidpulverulent product by mixing a powder of α tricalcium phosphate and apowder of tetracalcium phosphate. By powder of α tricalcium phosphate ismeant a powder containing at least 85% of phosphate of this form. The αtricalcium phosphate is much more soluble than the β form and leads to avery uniform and greater setting up and to the obtention of a paste ofimproved homogeneity.

Moreover, the aqueous solution is preferably prepared by mixingphosphoric acid and water with calcium hydroxide and/or calciumcarbonate. The use of these species avoids the presence of counter ionsin the obtained product and leads to the obtention of an apatite of highpurity (it is to be noted that, in acid medium, the carbonate iseliminated in the form of CO₂). The use of calcium carbonate leads to asolution having a pH of the order of 2.25, higher than if the calcium issupplied by hydroxide (pH of the solution of the order of 1.75). Thesetting up is slower in the first case. As the case may be, the mixtureof hydroxide and carbonate can be used to adjust the setup time to adesired value. This setup time can also be adjusted by the addition ofsmall quantities of acid suitable to lower the pH of the solutionwithout however reaching a value equal to or below 1 (a tendency tolumping appears below this value).

It is possible to add to the solid pulverulent product and/or to theaqueous solution, other additives adapted further to increase theregularity of setting up of the paste. For example, glycerophosphate,particularly sodium, potassium or calcium glycerophosphate, can be addedsuch that the weight percent of this compound relative to the finalmixture will be below 15%. This composition contributes to animprovement of the regularity of setting up and slightly decreases thespeed of setting up. In the case of calcium glycerophosphate, accountmust be taken of the ratio of calcium due to the addition of thiscompound to prepare and test initial products (pulverulent solidproduct, aqueous solution) so as to obtain a final atomic ratio Ca/Pcomprised within the mentioned range. The calcium surplus from thecalcium glycerophosphate can in particular be compensated by suitableaddition of phosphoric acid into the solution: this leads to a loweringof the pH of the solution and to a reduction of the setup time, whichmay be desirable in certain applications.

There can also be added to the solid pulverulent product and to theaqueous solution, lactic acid, such that the weight percent of thiscompound relative to the final mixture will be below 4%. This compoundhas a double effect: an immediate effect consisting in slowing thecrystallization of the mixture and increasing the regularity of settingand increasing the duration of the latter, and a final effect duringhardening arising from the formation of lactate and producing a materialof increased hardness.

It is also possible to add to the solid pulverulent product and/or tothe aqueous solution, an alginate or a guar gum, or chitosan, such thatthe weight percent of the compound relative to the final mixture will beless than 2%. These compounds increase the setup time and permit, as thecase may be, adapting the latter to a suitable value. Moreover, theygive the obtained mixture Theological properties of sliding, renderingthe mixture adept to circulate in conduits or passages particularly forits injection at the utilization site. Moreover, chitosan influences thechemical and crystallographic evolution of the paste obtained bystabilizing a portion of the latter at a preapatitic stage: there isthus obtained a crystalline biomaterial very near to that of bone,having a higher resorbability.

Moreover, the combination of the properties of microporosity of theobtained material and resorbability of the latter in vivo render saidmaterial well adapted to be loaded with an active substance so as toensure its in situ release, by diffusion and the resorption effect ofthe material. Such an active substance added to the solid pulverulentproperty in a quantity sufficient to obtain the desired result, can inparticular be constituted by an antibiotic, an antimitotic (particularlyfor material adapted to fill a cancerous tumor), or a growth factor(particularly in the case of filling bones so as to accelerate theregeneration of the bone).

The process of the invention is particularly well adapted for theproduction of a filling or a restoration at a dental or surgical site.The mixture of the aqueous solution and/or the solid pulverulent productis produced at ambient temperature, and the obtained paste is thenemplaced in the dental or bone site so as to ensure its hardening at 37°C. The solid pulverulent product and the aqueous solution are thenprepared in a batch as already indicated and loaded into two closedsterilized containers. One of the additives defined above can be addedto said batches, in particular sodium, potassium or calciumglycerophosphate, to the solid pulverulent product.

According to an embodiment suitable for surgical uses, the surgical setavailable to the surgeon comprises:

(a) for a set of a mean weight of 20 g:

a batch of solid pulverulent product containing between 4.20 and 4.50 gof α tricalcium phosphate, between 5.50 and 5.80 g of tetracalciumphosphate, and as the case may be between 1.4 and 1.6 g of sodium,potassium or calcium glycerophosphate,

a batch of aqueous solution containing between 0.18 and 0.22 g ofcalcium hydroxide and between 1.30 and 1.50 g of phosphoric acid insolution between 3.8 and 4.2 g of water.

(b) for a set of mean weight of 40 g: batches equal to twice the abovebatches,

(c) for a set of mean weight of 80 g: batches equal to four times theabove batches (a).

Such a surgical set permits in particular the surgeon to carry outinterventions under the best conditions: filling of bone defects,refection of the tibial plateau, additive osteotomy, sealing prostheses,refection of the cotyle base, and in most cases, grafting by means ofthe material avoiding the need for autological graft.

According to another embodiment suitable for dental applications, theset comprises:

(a) for a set of mean weight of 1.5 g:

a batch of solid pulverulent product containing between 0.42 and 0.45 gof α tricalcium phosphate, between 0.55 and 0.58 g of tetracalciumphosphate, and as the case may be, between 0.14 and 0.6 g of sodium,potassium or calcium glycerophosphate,

a batch of aqueous solution containing between 0.02 and 0.025 g ofcalcium hydroxide and between 0.13 and 0.15 g of phosphoric acid insolution in 0.3 to 0.4 g of water.

(b) for a set of mean weight of 3 g: batches equal to twice the abovebatches.

Such a dental set permits in particular a practitioner to carry outinterventions under the best conditions: filling of periodontal pockets,filling gaps, rebuilding ridges . . .

The following examples illustrate the process of the invention and theproperties of the obtained biomaterial, the ratio L/S indicated in theseexamples corresponds to the liquid/solid weight ratio of the pastymixture, designated cement, before hardening.

EXAMPLE 1 Preparation of a Cement Ca/P=1.67; L/S=0.45; NaGP=0%

The preparation in question corresponds to a preparation for a finalquantity of 145 g.

a) There is first prepared a mixture of powder by exact weight,comprising the following constituents:

Tetracalcium phosphate=62.38 g (tetracalcium phosphate is first crushedsuch that its granulometry will be less than 70 microns).

α tricalcium phosphates=37.62 g.

The calcium/phosphate atomic ratio of this mixture is equal to 1.79.

This mixture is carefully homogenized by means of a powder mixture.

There is then prepared a solution in the following manner:

b) There are measured 6.1 g of concentrated phosphoric acid (d=1.69);there is slowly added 1.46 g of calcium hydroxide. It is then completedwith 45 ml of distilled water. There is thus obtained an initial clearsolution, stable, of a calcium/phosphorus atomic ratio Ca/P=0.377.

c) The powder mixture is poured into a small mortar. All of the solutionis then added while vigorously stirring with a pestle or a spatula. Themixture is initially granular but becomes very quickly smooth andhomogeneous. After about one to two minutes of mixing, the mixture isleft to stand. After about 10 minutes it has a consistency such that itcan be molded and emplaced. It completes its setup after about 15minutes.

The cement prepared according to this method has an overall atomic ratioCa/P=1.67 and a liquid/solid ratio L/S=0.45.

If it is desired to examine the progress of this cement in vitro, it isnecessary to observe the hardening of the cement in a humid medium(analogous to that encountered in a biological medium).

The development of the cement from a crystallographic point of view, canbe followed by x-ray detraction. There is observed the progressivedisappearance of the initial phases of the mixture and the formationafter about 72 hours of an apatitic phase moderately crystallized; thisphase is analogous to that of the mineral portion of the bone.

Throughout the development of the mixture, the modifications of theplasticity can be measured by using a penetrometer: the latter measuresthe resistance to penetration at the surface of the cement of a 1 mm²point. It is considered that a value of about 250 g/mm² corresponds tothe limit for emplacing the cement at the utilization site. At a valuecorresponding to 300 g/mm², the cement has lost all malleability: it istotally set up. Of course, then it continues its hardening.

In the case of the cement described here, the limit value (250 g/mm²) isreached after 15 minutes. The resistance to compression is 15 MPa. Itsporosity is 41%.

EXAMPLE 2 Preparation of a Cement Ca/P=1.546; L/S=0.45; NaGP=0%

The proposed preparation corresponds to a preparation for a finalquantity of 145 g.

a) There is first prepared a powder mixture of exact weight comprisingthe following constituents:

Tetracalcium phosphates=16.8 g. The tetracalcium phosphate is groundsuch that its granulometry is less than 70 micron.

α tricalcium phosphates=83.3 g, such that the calcium/phosphorous atomicratio of this mixture will be equal to 1.573.

This mixture is carefully homogenized by means of a powder mixture.

There is then prepared a solution in the following manner:

b) 1.67 g (1 ml) of concentrated phosphoric acid is measured out(d=1.69); there is slowly added 0.40 g of calcium hydroxide. The mixtureis brought up to 45 ml with distilled water. There is thus obtained aclear solution, stable in its calcium/phosphorus atomic ratioCa/P=0.378.

c) There is poured into a small mortar the mixture of powder. There isthen added all of the solution while energetically mixing by means of apestle or a spatula. The mixture is initially granular but very quicklybecomes smooth and homogeneous. After about one to two minutes ofmixing, the mixture is left to stand. After about 25 minutes there is aconsistency such that it can be molded in place. Its setting up iscomplete after about 35 minutes.

The cement prepared according to this second method has an overallatomic ratio Ca/P=1.546 and a liquid/solid ratio L/S=0.45.

In the case of this cement, the limit value (250 g/mm²) is reached after30 minutes. The resistance to compression is 8 Mpa. Its porosity is 45%.

EXAMPLE 3 Ca/P=1.63; L/S=0.42; NaGP=4.5%

The following cement is prepared as the previous ones. The compositionof the different portions is:

Solid pulverulent phase:

Tetracalcium phosphate 16.8 g.

α tricalcium phosphate=83.3 g.

Sodium glycerophosphate (NaGP)=65 g such that the atomic ratio ofcalcium/phosphor of this mixture will be equal to 1.76.

Liquid phase:

Phosphoric acid (d=1.69)=2.47 g.

Calcium hydroxide=1.50 g.

Made up to 43 cm³ with distilled water.

The atomic ratio of the liquid is 0.367.

After this mixing, the paste sets up in 15 minutes. It final hardness is20 Mpa.

EXAMPLE 4 Ca/P=1.67; L/S=0.43; NaGP=9%

The following cement is prepared as above. The composition of thedifferent parts is:

Pulverulent solid phase:

Tetracalcium phosphate=49.0 g.

α tricalcium phosphate=37.8 g.

Sodium glycerophosphate (NaGP)=130 g such that the calcium/phosphateatomic ratio of this mixture will be equal to 1.76.

Liquid phase:

Phosphoric acid (d=1.69)=1.0 g

Calcium hydroxide=1.44 g made up to 43 cm³ with distilled water.

The atomic ratio of the liquid is 0.367.

After mixing, the paste sets up in 15 minutes. Its final hardness is 20Mpa. Its porosity is 40%.

EXAMPLE 5 Ca/P=1.58; L/S=0.45; NaGP 9%; Ca/P=1.546; L/S 0.45; NaGP=0%

The following cement is prepared as the previous ones. The differentcomposition of the portions is:

Solid pulverulent phase:

Tetracalcium phosphate=49.0 g

α tricalcium phosphate=62.0 g.

Sodium glycerophosphate (NaGP)=13 g such that the calcium/phosphorusratio of this mixture will be equal to 1.727.

Liquid phase:

Phosphoric acid (d=1.99)=0.6 ml.

Calcium hydroxide=1.44 g made up to 43 ml with distilled water.

The atomic ratio of the liquid is 0.377.

After mixing, the paste sets up in 20 minutes. Its final hardness is 10Mpa. Its porosity is 48%.

EXAMPLE 6

There is industrially prepared in the following manner quantities of 2kg of powder and 1000 cm³ of solution containing respectively:

Solid pulverulent product:

Tetracalcium phosphate=980 g.

α tricalcium phosphate=758.0 g

Glycerophosphate=260 g.

Solution:

Calcium hydroxide=34.0 g.

Phosphoric acid (d=1.69)=138 g.

Completed to 1000 cm³.

From these products are prepared surgical sets containing:

11.6 g of pulverulent solid in a bottle having 5 cm³ (that is 5.8 g) ofsolution in a sealed ampule. The whole is placed in a cardboard box,reference and sterilized by ionizing radiation.

From these products are prepared dental sets containing:

1.0 g of solid pulverulent in a closed bottle and 0.5 cm³ of solution ina sealed ampule.

EXAMPLE 7 Preparation of a Cement Containing Chitosan, such that:Ca/P=1.63; L/S=0.43; NaGP=9%; Chitosan 0.5%

The cement is prepared as before, the compositions of different portionsare as follows:

Solid

Tetracalcium phosphate: 49.0 g

α tricalcium phosphate: 37.9 g

Sodium glycerophosphate: 13 g

Solution

Calcium hydroxide: 3.4 g

Phosphoric acid (d: 1.69)=13.8 g

Chitosan (Deacelated to 50%)=1 g

Completed to 100 ml

11.6 g of pulverulent solid are mixed with 5 ml of the solution. Thewhole is ground for 1 minute. After a duration of 15 minutes, the cementhas sufficient hardness to be emplaced in a surgical site; however, itssetting up is not complete until after 1 hour.

When hardening is carried out under moist conditions analogous to thosein a biological medium, the cement after one full day of development hasa crushing strength equal to 20 Mpa.

X ray diffraction carried out after 24 hours and after one week, showthat the evolution toward the apatite phase is not total. A portion ofthe cement has evolved toward a pre-apatite phase of the octocalciumphosphate type.

What is claimed is:
 1. A process for the preparation of a biomaterialcomprising a hardening phase at a utilization site, in which calciumphosphates are mixed to obtain a hydroxy apatite with an atomic ratioCa/P of between 1.50 and 1.67, the process comprising the steps of: (a)mixing a tricalcium phosphate powder and a tetracalcium phosphate powderto obtain a solid pulverulent product having an atomic ratio Ca/P ofbetween 1.40 and 1.90; (b) preparing an aqueous solution or solutionscontaining calcium ions and phosphate ions having an overall atomicratio Ca/P of the solutions greater than 0.20 and the atomic ratio Ca/Pof each solution less than 0.50; and (c) mixing the aqueous solution orsolutions, the solid pulverulent product and optionally water to obtaina final mixture with a liquid/solid weight ratio of between 0.30 and0.65 so as to obtain a homogeneous paste of an atomic ratio Ca/P ofbetween 1.50 and 1.67, the paste being emplaced at the utilization sitefor in situ hardening.
 2. The process according to claim 1, wherein abatch of the solid pulverulent product is obtained from step (a), abatch of an aqueous solution containing both calcium ions and phosphateions is prepared from step (b), the batches of solid product and ofaqueous solution having an overall liquid/solid weight ratio of between0.30 and 0.65 and an overall atomic ratio Ca/P of between 1.50 and 1.67,and in step (c) the batch of solid pulverulent product and the batch ofaqueous solution are mixed homogeneously without the addition of water.3. The process according to claim 1, wherein the solid pulverulentproduct from step (a) has a mean diameter of the grains D50 of between15 and 50 microns and a cutting diameter D95 equal to 100 microns. 4.The process according to claim 1, wherein the tricalcium phosphatepowder comprises α tricalcium phosphate powder.
 5. The process accordingto claim 1, wherein the aqueous solution is prepared by mixing in water,phosphoric acid with at least one of calcium hydroxide and calciumcarbonate.
 6. The process according to claim 1, further comprisinglowering the pH of the aqueous solution by adding a small quantity ofacid with the pH of the solution remaining greater than
 1. 7. Theprocess according to claim 1, wherein the solid pulverulent product hasan atomic ratio Ca/P of between 1.70 and 1.85 and the aqueous solutionhas an atomic ratio Ca/P of between 0.35 and 0.40.
 8. The processaccording to claim 1, further comprising adding a glycerophosphate to atleast one of the solid pulverulent product and the aqueous solution, theweight percentage of the glycerophosphate in the final mixture beingless than 15% wherein said glycerophospate is added in a manner so thatthe final atomic ratio of Ca/P is between 1.50 and 1.67 and theliquid/solid weight ratio is between 0.30 and 0.65.
 9. The processaccording to claim 1, further comprising adding lactic acid to at leastone of the solid pulverulent product and the aqueous solution, theweight percent of the lactic acid in the final mixture being less than4%.
 10. The process according to claim 1, further comprising adding atleast one element selected from the group consisting of an alginate,guar gum and chitosan to at least one of the solid pulverulent productand the aqueous solution, the weight percentage of the elements in thefinal mixture being less than 2%.
 11. The process according to claim 1,further comprising adding an active substance selected from the groupconsisting of an antibiotic substance, an antimitotic substance and agrowth factor substance to the solid pulverulent product.
 12. Theprocess according to claim 1, wherein step (c) is performed at ambienttemperature, the mixture hardening at a temperature below 40° C.
 13. Theprocess according to claim 1, wherein to produce by molding a piece forsurgical or prosthetic use, step (c) is performed at ambienttemperature; depositing the mixture in a mold at ambient temperature toobtain a piece; and removing the piece from the mold and heating thepiece to a temperature between 50° C. and 90° C. in a moist or aqueousatmosphere to obtain complete hardening.
 14. Surgical or dental set,comprising: a first batch of a solid pulverulent product comprising amixture of tricalcium phosphate and tetracalcium phosphate with anatomic ratio Ca/P of between 1.40 and 1.90, the first batch packaged ina first closed sterilized container; and a second batch of an aqueoussolution containing calcium ions and phosphate ions with an atomic ratioCa/P of between 0.20 and 0.50, the second batch being packaged in asecond closed sterilized container; the first and second batches havingan overall liquid/solid weight ratio of between 0.30 and 0.65 and anoverall atomic ratio Ca/P of between 1.50 and 1.67.
 15. The surgical ordental set according to claim 14, wherein the first batch contains aweight percent of sodium, potassium or calcium glycerophosphate ofbetween 5 and 15% wherein said glycerophospate is added in a manner sothat the final atomic ratio of Ca/P is between 1.50 and 1.67 and theliquid/solid weight ratio is between 0.30 and 0.65.